Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

ABSTRACT

The invention relates to carboxamide-substituted phenylurea derivatives and their physiologically tolerated salts and physiologically functional derivatives.  
     Compounds of the formula I  
                 
 
     in which the radicals have the stated meanings, and the physiologically tolerated salts thereof and process for their preparation are described. The compounds are suitable, for example, for treating type II diabetes.

[0001] This application claims the benefit of foreign priority under 35U.S.C. §119 of German patent application no. 10125567.5, filed on May25, 2001 and German patent application no10207369.4, filed on Jan. 22,2002 the contents of both of which are incorporated by reference herein.

[0002] The invention relates to carboxamide-substituted phenylureaderivatives and their physiologically tolerated salts andphysiologically functional derivatives.

[0003] Acylphenylurea derivatives of similar structure have already beendescribed in the prior art as insecticides (EP 0 136 745, EP 0 167 197,DE 29 26 480, J. Agric. Food Chem. 1999, 47, 3116-3424).

[0004] In one embodiment, the invention is based on the object ofproviding compounds which display a blood glucose-lowering effect whichcan be utilized in therapy.

[0005] The invention therefore, for example, relates to compounds of theformula I,

[0006] in which

[0007] A is phenyl or naphthyl, where the phenyl or naphthyl isunsubstituted or substituted 1, 2, or 3 times wherein each substituentis independently chosen from F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀C₆)-alkylene-COOH,(C₀C₆)-alkylene-COO—(C₁-C₇)-alkyl, (C₀-C₆)-alkylene-COO—(C₂-C₇)-alkenyl,CONH₂, CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂,CONH—(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH—(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N—[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, and NH—SO₂-phenyl, wherein the phenylof NH—CO-phenyl and NH—SO₂-phenyl is unsubstituted or substituted 1 or 2times wherein each substituent is independently chosen from F, Cl, CN,OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyland CONH₂;

[0008] R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, or COO—(C₁-C₆)-alkyl;

[0009] R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl,O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—NH₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂,CO—NH—(C₁-C₆)-alkyl, CO—N—[(C₁-C₆)-alkyl]₂, CO—NH—(C₃-C₇)-cycloalkyl,NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenyl of NH—CO-phenyl andNH—SO₂-phenyl is unsubstituted or substituted 1 or 2 times wherein eachsubstituent is independently chosen from F, Cl, CN, OH, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl and CO—NH₂;

[0010] R7 is H, (C₁-C₆)-alkyl, or CO(C₁-C₆)-alkyl;

[0011] R8 is H, (C₁-C₁₀)-alkyl, where the alkyl is unsubstituted orsubstituted 1, 2, or 3 times wherein each substituent is independentlychosen from OH, CF₃, CN, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂,NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NCO—(C₁-C₆)-alkyl,NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl, NCOO—(C₁-C₆)-alkynyl andNCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or

[0012] (CH₂)_(m)-aryl, where m ranges from 0-6, and aryl is phenyl,O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl,indolyl, piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,or morpholinyl, where the aryl is unsubstituted or substituted by atleast one R9;

[0013] R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COOH, or COO—(C₁-C₆)-alkyl;

[0014] and their physiologically tolerable salts.

[0015] In one embodiment, the compounds of the formula I are those inwhich

[0016] A is phenyl, where the phenyl is unsubstituted or substituted 1,2, or 3 times wherein each substituent is independently chosen from F,Cl, and Br;

[0017] R1, R2 are H;

[0018] R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,NO₂, O—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl;

[0019] R7 is H, or CH₃;

[0020] R8 is H, (C₁-C₁₀)-alkyl, where the alkyl is unsubstituted orsubstituted 1, 2, or 3 times wherein each substituent is independentlychosen from OH, CF₃, CN, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂,NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NCO—(C₁-C₆)-alkyl,NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl, NCOO—(C₁-C₆)-alkynyl orNCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or

[0021]  (CH2)_(m)-aryl, where m ranges from 0-6, and aryl is phenyl,O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl,indolyl, piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,morpholinyl, where the aryl is unsubstituted or substituted by at leastone R9;

[0022] R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COOH, or COO—(C₁-C₆)-alkyl;

[0023] and their physiologically tolerable salts.

[0024] In another embodiment, the compounds of the formula I are thosein which

[0025] A is phenyl, where the phenyl is unsubstituted or substituted 1,2, or 3 times wherein each substituent is independently chosen from F,Cl, and Br;

[0026] R1, R2 are H;

[0027] R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,NO₂, O—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl;

[0028] R7 is H, or CH₃;

[0029] R8 is (C₁-C₁₀)-alkyl, where the alkyl is unsubstituted orsubstituted 1, 2, or 3 times wherein each substituent is independentlychosen from OH, CF₃, CN, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂,NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NCO—(C₁-C₆)-alkyl,NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl, NCOO—(C₁-C₆)-alkynyl orNCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or

[0030]  (CH₂)_(m)-aryl, where m ranges from 0-6, and aryl is phenyl,O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl,indolyl, piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,morpholinyl, where the aryl is unsubstituted or substituted by at leastone R9;

[0031] R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COOH, or COO—(C₁-C₆)-alkyl;

[0032] and their physiologically tolerable salts.

[0033] In one embodiment, the invention further relates to the use ofthe compounds of the formula I

[0034] in which

[0035] A is phenyl or naphthyl, where the phenyl or naphthyl isunsubstituted or substituted 1, 2, or 3 times wherein each substituentis independently chosen from F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀C₆)-alkylene-COOH,(C₀C₆)-alkylene-COO—(C₁-C₇)-alkyl, (C₀-C₆)-alkylene-COO—(C₂-C₇)-alkenyl,CONH₂, CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂,CONH—(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH—(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-N—[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, NH—SO₂-phenyl, wherein the phenyl ofNH—CO-phenyl and NH—SO₂-phenyl is unsubstituted or substituted 1 or 2times wherein each substituent is independently chosen from F, Cl, CN,OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyland CONH₂;

[0036] R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, or COO—(C₁-C₆)-alkyl;

[0037] R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl,O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—NH₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂,CO—NH—(C₁-C₆)-alkyl, CO—N—[(C₁-C₆)-alkyl]₂, CO—NH—(C₃-C₇)-cycloalkyl,NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenyl of NH—CO-phenyl andNH—SO₂-phenyl is unsubstituted or substituted 1 or 2 times wherein eachsubstituent is independently chosen from F, Cl, CN, OH, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl and CO—NH₂;

[0038] R7 is H, (C₁-C₆)-alkyl, or CO(C₁-C₆)-alkyl;

[0039] R8 is H, (C₁-C₁₀)-alkyl, where the alkyl is unsubstituted orsubstituted 1, 2, or 3 times wherein each substituent is independentlychosen from OH, CF₃, CN, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂,NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NCO—(C₁-C₆)-alkyl,NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl, NCOO—(C₁-C₆)-alkynyl orNCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or

[0040]  (CH₂)_(m)-aryl, where m can be 0-6, and aryl can be phenyl,O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl,indolyl, piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,morpholinyl, where the aryl is unsubstituted or substituted by at leastone R9;

[0041] R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COOH, or COO—(C₁-C₆)-alkyl;

[0042] and their physiologically tolerable salts, for producing amedicament for reducing the blood glucose level and treating type IIdiabetes. In another embodiments, these compounds are useful in methodsfor reducing the blood glucose level and treating type II diabetes of amammal, for example a human.

[0043] The compounds of the formula I may be present in the form oftheir racemates, racemic mixtures, pure enantiomers, and diastereomers,and mixtures thereof. The alkyl radicals in the substituents R1, R2, R3,R4, R5, R6, R7, R8, R9 and A may be both straight-chain and branched.

[0044] Pharmaceutically acceptable salts may be particularly suitablefor medical applications because of their greater solubility in watercompared with the starting or base compounds. In one embodiment, thesesalts must have a pharmaceutically acceptable anion or cation. Suitablepharmaceutically acceptable acid addition salts of the compounds of theinvention are salts of inorganic acids such as hydrochloric acid,hydrobromic, phosphoric, metaphosphbric, nitric and sulfuric acids, andof organic acids such as, for example, acetic acid, benzenesulfonic,benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,isethionic, lactic, lactobionic, maleic, malic, methanesulfonic,succinic, p-toluenesulfonic and tartaric acids. Suitablepharmaceutically acceptable basic salts are ammonium salts, alkali metalsalts (such as sodium and potassium salts) and alkaline earth metalsalts (such as magnesium and calcium salts).

[0045] Salts with a pharmaceutically unacceptable anion such as, forexample, trifluoroacetate likewise belong within the scope of theinvention as useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

[0046] The term “physiologically functional derivative” used hereinrefers to any physiologically tolerated derivative of a compound of theformula I of the invention, for example an ester which is able, onadministration to a mammal such as, for example, to a human, to form(directly or indirectly) a compound of the formula I or an activemetabolite thereof.

[0047] Physiologically functional derivatives also include prodrugs ofthe compounds of the invention, as described, for example, in H. Okadaet al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves have activity or not.

[0048] The compounds of the invention may also exist in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds of theinvention belong within the scope of the invention and are a furtheraspect of the invention.

[0049] All references hereinafter to “compound(s) of formula I” refer tocompound(s) of the formula I as described above, and to the salts,solvates and physiologically functional derivatives thereof as describedherein.

[0050] The compound(s) of the formula (I) may also be administered incombination with other active ingredients.

[0051] The amount of a compound of formula I necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. In oneembodiment, the daily dose is generally in the range from 0.3 mg to 100mg (typically from 3 mg to 50 mg) per day and per kilogram ofbodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, forexample, in the range from 0.3 mg to 1.0 mg/kg, which can suitably beadministered as infusion of 10 ng to 100 ng per kilogram and per minute.Suitable infusion solutions for these purposes may contain, for example,from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.Single doses may contain, for example, from 1 mg to 10 g of the activeingredient. Thus, ampoules for injections may contain, for example, from1 mg to 100 mg, and single-dose formulations which can be administeredorally, such as, for example, capsules or tablets, may contain, forexample, from 1.0 to 1000 mg, typically from 10 to 600 mg. For thetherapy of the abovementioned conditions, the compounds of formula I maybe used as the compound itself, but they are preferably in the form of apharmaceutical composition with an acceptable carrier. The carrier must,of course, be acceptable in the sense that it is compatible with theother ingredients of the composition and is not harmful for thepatient's health. The carrier may be a solid or a liquid or both and ispreferably formulated with the compound as a single dose, for example asa tablet, which may contain from 0.05% to 95% by weight of the activeingredient. Other pharmaceutically active substances may likewise bepresent, including other compounds of formula I. The pharmaceuticalcompositions of the invention can be produced by one of the knownpharmaceutical methods, which may essentially consist of mixing theingredients with pharmacologically acceptable carriers and/orexcipients.

[0052] Pharmaceutical compositions of the invention are those suitablefor oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable mode ofadministration depends in each individual case on the nature andseverity of is the condition to be treated and on the nature of thecompound of formula I used in each case. Coated formulations and coatedslow-release formulations also belong within the framework of theinvention. Preference is given to acid- and gastric juice-resistantformulations. Suitable coatings resistant to gastric juice comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0053] In one embodiment, suitable pharmaceutical compounds for oraladministration may be in the form of separate units such as, forexample, capsules, wafers, suckable tablets or tablets, each of whichcontain a defined amount of the compound of formula I; as powders orgranules, as solution or suspension in an aqueous or nonaqueous liquid;or as an oil-in-water or water-in-oil emulsion. These compositions may,as already mentioned, be prepared by any suitable pharmaceutical methodwhich includes a step in which the active ingredient and the carrier(which may consist of one or more additional ingredients) are broughtinto contact. The compositions are generally produced by uniform andhomogeneous mixing of the active ingredient with a liquid and/or finelydivided solid carrier, after which the product is shaped if necessary.Thus, for example, a tablet mau be produced by compressing or molding apowder or granules of the compound, where appropriate with one or moreadditional ingredients. Compressed tablets may be produced by tabletingthe compound in free-flowing form such as, for example, a powder orgranules, where appropriate mixed with a binder, glidant, inert diluentand/or one or more surface-active/dispersing agent(s) in a suitablemachine. Molded tablets may be produced by molding the compound which isin powder form and is moistened with an inert liquid diluent in asuitable machine.

[0054] In one embodiment, pharmaceutical compositions which are suitablefor peroral (sublingual) administration comprise suckable tablets whichcontain a compound of formula I with a flavoring, normally sucrose andgum arabic or tragacanth, and pastilles which comprise the compound inan inert base such as gelatin and glycerol or sucrose and gum arabic.

[0055] The pharmaceutical compositions suitable for parenteraladministration may, for example, comprise sterile aqueous preparationsof a compound of formula I, which are isotonic with the blood of theintended recipient. These preparations may be administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationsmay may be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

[0056] Pharmaceutical compositions suitable for rectal administrationmay be, for example, in the form of single-dose suppositories. These maybe produced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

[0057] Pharmaceutical compositions suitable for topical use on the skinare preferably in the form of ointment, creme, lotion, paste, spray,aerosol or oil. Carriers which can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5 to 2%.

[0058] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal uses may be in the form of singleplasters which are suitable for long-term close contact with thepatient's epidermis. Such plasters, for example, suitably contain theactive ingredient in an aqueous solution which is buffered whereappropriate, dissolved and/or dispersed in an adhesive or dispersed in apolymer. A suitable active ingredient concentration is, for example,about 1% to 35%, preferably about 3% to 15%. One embodiment, is for theactive ingredient to be released by electrotransport or iontophoresis asdescribed, for example, in Pharmaceutical Research, 2(6): 318 (1986).

[0059] Further active ingredients suitable for combination products are:all antidiabetics mentioned in chapter 12 of the Rote Liste 2001. Theymay be combined with the compounds of the formula I of the invention inparticular for synergistic improvement of the effect. Administration ofthe active ingredient combination may take place either by separateadministration of the active ingredients to the patients or in the formof combination products in which a plurality of active ingredients arepresent in one pharmaceutical preparation.

[0060] Antidiabetics include insulin and insulin derivatives such as,for example, Lantus® or HMR 1964, GLP-1 derivatives such as, forexample, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orallyactive hypoglycemic active ingredients.

[0061] The orally active hypoglycemic active ingredients include, forexample, sulfonylureas, biguamides, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, potassium channel openers such as, for example, thosedisclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulinsensitizers, inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, modulators of glucose uptake,compounds which alter lipid metabolism, such as antihyperlipidemicactive ingredients and antilipidemic active ingredients, compounds whichreduce food intake, PPAR and PXR agonists and active ingredients whichact on the ATP-dependent potassium channel of the beta cells.

[0062] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an HMG-COA reductase inhibitorsuch as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin.

[0063] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a cholesterol absorptioninhibitor such as, for example, ezetimibe, tiqueside, pamaqueside.

[0064] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a PPAR gamma agonist such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI 262570.

[0065] In one embodiment of the invention, the compounds of the formulaI are administered in combination with PPAR alpha agonist such as, forexample, GW 9578, GW 7647.

[0066] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a mixed PPAR alpha/gamma agonistsuch as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.

[0067] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a fibrate such as, for example,fenofibrate, clofibrate, bezafibrate.

[0068] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an MTP inhibitor such as, forexample, Bay 13-9952, BMS-201038, R-103757.

[0069] In one embodiment of the invention, the compounds of the formulaI are administered in combination with bile acid adsorption inhibitorsuch as, for example, HMR 1453.

[0070] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a CETP inhibitor such as, forexample, Bay 194789.

[0071] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a polymeric bile acid adsorbentsuch as, for example, cholestyramine, colesevelam.

[0072] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an LDL receptor inducer such as,for example, HMR1171, HMR1586.

[0073] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ACAT inhibitor such as, forexample, avasimibe.

[0074] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an antioxidant such as, forexample, OPC-14117.

[0075] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein lipase inhibitorsuch as, for example, NO-1886.

[0076] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ATP citrate lyase inhibitorsuch as, for example, SB-204990.

[0077] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a squalene synthetase inhibitorsuch as, for example, BMS-188494.

[0078] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein(a) antagonist suchas, for example, CI-1027 or nicotinic acid.

[0079] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipase inhibitor such as, forexample, orlistat.

[0080] In one embodiment of the invention, the compounds of the formulaI are administered in combination with insulin.

[0081] In one embodiment, the compounds of the formula I areadministered in combination with a sulfonylurea such as, for example,tolbutamide, glibenclamide, glipizide or gliclazide.

[0082] In one embodiment, the compounds of the formula I areadministered in combination with a biguamide such as, for example,metformin.

[0083] In another embodiment, the compounds of the formula I areadministered in combination with a meglitinide such as, for example,repaglinide.

[0084] In one embodiment, the compounds of the formula I areadministered in combination with a thiazolidinedione such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone or thecompounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.

[0085] In one embodiment, the compounds of the formula I areadministered in combination with an α-glucosidase inhibitor such as, forexample, miglitol or acarbose.

[0086] In one embodiment, the compounds of the formula I areadministered in combination with an active ingredient which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, gliclazide or repaglinide.

[0087] In one embodiment, the compounds of the formula I areadministered in combination with more than one of the aforementionedcompounds, for example in combination with a sulfonylurea and metformin,a sulfonylurea and acarbose, repaglinide and metformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

[0088] In a further embodiment, the compounds of the formula I areadministered in combination with CART agonists, NPY agonists, MC4agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRFBP antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, CCK agonists, serotoninreuptake inhibitors, mixed serotoninergic and noradrenergic compounds,5HT agonists, bombesin agonists, galanin antagonists, growth hormone,growth hormone-releasing compounds, TRH agonists, decoupling protein 2or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors, PPAR modulators, RXR modulators orTR-βagonists.

[0089] In one embodiment of the invention, the other active ingredientis leptin.

[0090] In one embodiment, the other active ingredient is dexamphetamineor amphetamine.

[0091] In one embodiment, the other active ingredient is fenfluramine ordexfenfluramine.

[0092] In a further embodiment, the other active ingredient issibutramine.

[0093] In one embodiment, the other active ingredient is orlistat.

[0094] In one embodiment, the other active ingredient is mazindol orphentermine.

[0095] In one embodiment, the compounds of the formula I areadministered in combination with dietary fiber materials, preferablyinsoluble dietary fiber materials such as, for example, Caromax®.Combination with Caromax® is possible in one preparation or by separateadministration of compounds of the formula I and Caromax®. Caromax® canmoreover be administered in the form of foodstuffs such as, for example,in bakery products or muesli bars.

[0096] It is self-evident that any suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isregarded as falling within the protection conferred by the presentinvention.

[0097] The invention further relates to a process for the preparation ofthe compounds of the formula I, which comprises obtaining the compoundsof the formula I by proceeding in accordance with the following reactionscheme:

[0098] For this purpose, compounds of the formula II

[0099] in which

[0100] R9, R10, R11, R 12 are, independently of one another, H, F, Cl,Br, O—(PG-1), CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl,O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—N—(PG-2)₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COO—(PG-3), COO—(C₁-C₆)-alkyl,CON—(PG-2)₂, CO—NH—(C₁-C₆)-alkyl, CO—N—[(C₁-C₆)-alkyl]₂,CO—NH—(C₃-C₇)-cycloalkyl, N—(PG-2)₂, NH—(C₁-C₆)-alkyl,N—[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, andNH—SO₂-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO₂-phenyl isunsubstituted or substituted 1 or 2 times wherein each substituent isindependently chosen from F, Cl, CN, O—(PG-1), (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COO—(PG-3), COO—(C₁-C₆)-alkyl andCON—(PG-2)₂;

[0101] in which R2 has the meaning described above, and

[0102] PG-1 is a generally known protective group for alcohols, such as,for example, benzyl, allyl, tetrahydropyranyl or tetrahydrofuranyl;

[0103] PG-2 is a generally known protective group for amino groups, suchas, for example, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkyloxycarbonyl or(C₆-C₁₂)-aryl-(C₁-C₄)-alkyloxycarbonyl, which replaces either bothhydrogen atoms or only one hydrogen atom in the amino group;

[0104] PG-3 is a generally known protective group for esters, such as,for example, (C₁-C₆)-alkyl, benzyl or p-methoxybenzyl;

[0105] are reacted with isocyanates of the formula III

[0106] in which

[0107] A′ is phenyl or naphthyl, where the phenyl or naphthyl isunssubstituted or substituted 1, 2 or 3 times wherein each substituentis independently chosen from F, Cl, Br, O—PG-1, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—N-(PG-2)₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COO—(PG-3),(C₀-C₆)-alkylene-COO—(C₁-C₇)-alkyl,(C₀-C₆)-alkylene-COO—(C₂-C₇)-alkenyl, CO—N—(PG-2)₂, CO—NH—(C₁-C₆)-alkyl,CO—N—[(C₁-C₆)-alkyl]₂, CONH—(C₃-C₆)-cycloalkyl,(C₀-C₆)-alkylene-N—(PG-2)₂, (C₀C₆)-alkylene-NH—(C₁-C₆)-alkyl,(C₀-C₆)-alkylene-N—[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)— alkyl, NH—CO-phenyl,and NH—SO₂-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO₂-phenylis unsubstituted or substituted 1 or 2 times wherein each substituent isindependently chosen from F, Cl, CN, O—(PG-1), (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COO—(PG-3), COO—(C₁-C₆)-alkyl andCO—N-(PG-2)₂;

[0108] in which PG-3, PG-2 and PG-1 have the meaning described above,

[0109] in anhydrous organic solvents such as, for example, benzene,toluene or acetonitrile, under a protective gas atmosphere at reactiontemperatures between 10° C. and the boiling point of the solventemployed, to give compounds of the formula IV

[0110] in which R2, R9, R10, R11, R12, and A′ have the meaning describedabove.

[0111] Compounds of the formula IV are reacted with coupling reagentscustomary in peptide synthesis, such as, for example, carbodiimides suchas dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide,carbonyldiazoles such as carbonyldiimidazole and similar reagents,propylphosphonic anhydrides,O-((cyano(ethoxycarbonyl)methylene)amino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU) and many others, or with formation of the acidchloride, for example using thionyl chloride, with compounds of theformula V

[0112] in which R7 has the meaning described above, and

[0113] R13 is (C₁-C₁₀)-alkyl, where the alkyl is unsubstituted orsubstituted 1, 2 or 3 time wherein each substituent is independentlychosen from O—(PG-1), CF₃, CN, COO—(PG-3), COO—(C₁-C₆)-alkyl,CO—N—(PG-2)₂, NH—(PG-2), NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂; phenyl,O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl,indolyl, piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydrobenzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,and morpholinyl, where the rings are each independently unsubstituted orsubstituted by at least one R14;

[0114] R14 is F, Cl, Br; O—(PG-1), NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COO—(PG-3), or COO—(C₁-C₆)-alkyl;

[0115] to give compounds of the formula VI

[0116] the compounds of the formula VI can, if R1 in compounds of theformula I is not a hydrogen atom, be alkylated by reaction withcompounds of the formula VII

R15-LG  (VII)

[0117] in which

[0118] LG is a generally known leaving group such as, for example,halogen, arylsulfonyloxy or alkylsulfonyloxy;

[0119] and

[0120] R15 is (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, orCOO—(C₁-C₆)-alkyl,

[0121] using a base such as, for example,1,8-diazabicyclo[5.4.0]undec-7-ene, in organic solvents such as, forexample, dichloromethane or acetonitrile, to give compounds of theformula VIII

[0122] in which R2, R7, R9, R10, R11, R12, R13, R15 and A′ have themeaning described above,

[0123] and after elimination known from the literature of some or allprotective groups which may be present, for example, in the radicals R9,R10, R11, R12, R13, R14 and A′, compounds of the formula I are obtained.Compounds of the formula I are converted into the salts thereof byadding one equivalent of the appropriate acid or base in an organicsolvent such as, for example, acetonitrile or dioxane or in water and bysubsequent removal of the solvent.

[0124] Another possibility for preparing compounds of the formula I inwhich R2 is a hydrogen atom is depicted in the following scheme:

[0125] in which compounds of the formula XII

[0126] in which R9, R10, R11, R12 and PG-3 have the meaning describedabove, are converted into isocyanates of the formula X

[0127] by known methods, such as, for example, reaction with oxalylchloride in organic solvents such as, for example, 1,2-dichloroethane ordichloromethane, at reaction temperatures between room temperature andthe boiling point of the solvent, the isocyanates of the formula X arereacted with amides of the formula XI

[0128] in which A′ has the meaning described above, to result incompounds of the formula XII

[0129] in which R9, R10, R11, R12 and PG-3 have the meaning describedabove, compounds of the formula XII can, if R1 is not a hydrogen atom,be converted as described above by alkylation with compounds of theformula VII to give compounds of the formula XIII, selectivedeprotection of the COO—(PG-3) group and subsequent amide coupling withcompounds of the formula V to give compounds of the formula XIV and, ifnecessary, by subsequent elimination of the protective groups intocompounds of the formula I. Compounds of the formula I are convertedinto the salts thereof by addition of one equivalent of the appropriateacid or base in an organic solvent such as, for example, acetonitrile ordioxane or in water and by subsequent removal of the solvent.

[0130] The examples detailed below serve to illustrate the inventionwithout, however, restricting it. The measured solidification anddecomposition points (Fp.) have not been corrected and generally dependon the heating rate. TABLE 1 Examples

Ex. A R1* R2 R3 R4 R6 R5 Amide** R7 R8*** MS**** 1 Phenyl-2-Cl H H 2-Cl3-H 4-H 6-H 5 H

ok 2 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 3 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH₂)₅—OH ok 4 Phenyl-2-Cl H H2-H 4-H 5-H 6-H 3 H (CH₂)₆—OH ok 5 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 6 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 7 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 8 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 9 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 10 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 11 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 12 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH₂)₃—COOtBu ok 13Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 14 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H

ok 15 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH₂)₅—CH₃ ok 16 Phenyl-2-Cl HH 2-H 4-Cl 5-H 6-H 3 H (CH₂)₅—OH ok 17 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H3 H (CH₂)₆—OH ok 18 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H

ok 19 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H

ok 20 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H

ok 21 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H (CH₂)₅—CH₃ ok 22 Phenyl-2-ClH H 2-CH₃ 3-H 4-H 6-H 5 H

ok 23 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H (CH₂)₅—OH ok 24 Phenyl-2-ClH H 2-CH₃ 3-H 4-H 6-H 5 H (CH₂)₆—OH ok 25 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H6-H 5 H

ok 26 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 27 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 28 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 29 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 30 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 31 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 32 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 33 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H

ok 34 Phenyl-2-Cl H H 2-CH₃ 3-H 4-H 6-H 5 H (CH₂)₅—CH₃ ok 35 Phenyl-2-ClH H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 36 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 37 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₅—OH ok 38 Phenyl-2-ClH H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₆—OH ok 39 Phenyl-2-Cl H H 2-OCH₃ 3-H4-H 6-H 5 H

ok 40 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 41 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 42 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 43 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₅—CH₃ ok 44Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 45 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 46 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 47 Phenyl-2-Cl H H 2-H 4- NO₂ 5-H 6-H 3 H

ok 48 Phenyl-2-Cl H H 2-H 4- 5-H 6-H 3 H (CH₂)₅—OH ok NO₂ 49 Phenyl-2-ClH H 2-H 4- 5-H 6-H 3 H (CH₂)₆—OH ok NO₂ 50 Phenyl-2-Cl H H 2-H 4- 5-H6-H 3 H (CH₂)₅—CH₃ ok NO₂ 51 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H(CH₂)₃—COOH ok 52 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₃—COOH ok53 Phenyl-2,6-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 54 Phenyl-2,6-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 55 Phenyl-2,6-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 56 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 57 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 58 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 59 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 60 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 61 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 62 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 63 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 64 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 65 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 66 Phenyl-2-CI H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 67 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 68 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 69 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 70 Phenyl-2-Cl H H 2-H 4- NO₂ 5-H 6-H 3 H

ok 71 Phenyl-2-Cl H H 2-H 4- NO₂ 5-H 6-H 3 H

ok 72 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 73 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 74 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H CH₂—CF₃ ok 75 Phenyl-2-Cl HH 2-OCH₃ 3-H 4-H 6-H 5 H

ok 76 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 77 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 78 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 79 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₂—CH₃ ok 80Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 81 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 82 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 83 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 84 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 85 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 86 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 87 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 88 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 89 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 90 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 91 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 92 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 93 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 94 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 95 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 96 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 97 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 98 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 99 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 100 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 101 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 102 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 103 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 104 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 105 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₅—CN ok 106Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 107 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 108 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 109 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 110 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 111 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 112 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 113 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 114 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 115 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 116 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 117 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 118 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 119 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 120 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 121 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 122 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 123 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 124 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 125 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 126 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 127 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 128 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 129 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 130 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 131 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 132 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 133 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 134 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 135 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 136 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 137 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 138 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 139 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 140 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 141 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 142 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 143 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 144 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 145 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 146 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 147 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 148 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 149 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 150 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 151 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 152 Phenyl-2,4-Cl₂ Na H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 153 Phenyl-2-Cl H H 2-H 4-H 5-NO₂ 6-H 3 H (CH₂)₅—OH ok 154Phenyl-2-Cl H H 2-H 4-H 5-NO₂ 6-H 3 H (CH₂)₆—OH ok 155 Phenyl-2-Cl H H2-H 4-H 5-NO₂ 6-H 3 H

ok 156 Phenyl-2-Cl H H 2-H 4-H 5-NO₂ 6-H 3 H

ok 157 Phenyl-2-Cl H H 2-F 4-F 5-F 6-H 3 H

ok 158 Phenyl-2-Cl H H 2-F 4-F 5-F 6-H 3 H

ok 159 Phenyl-2-Cl H H 2-F 4-F 5-F 6-H 3 H

ok 160 Phenyl-2-Cl H H 2-F 3-H 4-H 6-H 5 H (CH₂)₅—OH ok 161 Phenyl-2-ClH H 2-F 3-H 4-H 6-H 5 H

ok 162 Phenyl-2-Cl H H 2-F 3-H 4-H 6-H 5 H

ok 163 Phenyl-2-Cl H H 2-F 3-H 4-H 6-H 5 H

ok 164 Phenyl-2,4-Cl₂ H H 2-H 4-H 5-NO₂ 6-H 3 H (CH₂)₅—OH ok 165Phenyl-2,4-Cl₂ H H 2-F 4-F 5-F 6-H 3 H (CH₂)₅—OH ok 166 Phenyl-2,4-Cl₂ HH 2-F 4-F 5-F 6-H 3 H (CH₂)₆—OH ok 167 Phenyl-2,4-Cl₂ H H 2-F 3-H 4-H6-H 5 H (CH₂)₅—OH ok 168 Phenyl-2,4-Cl₂ H H 2-F 3-H 4-H 6-H 5 H(CH₂)₆—OH ok 169 Phenyl-2,4-Cl₂ H H 2-F 3-H 4-H 6-H 5 H

ok 170 Phenyl-2,4-Cl₂ H H 2-F 3-H 4-H 6-H 5 H

ok 171 Phenyl-2,4-Cl₂ H H 2-F 3-H 4-H 6-H 5 H

ok 172 Phenyl-2,4-Cl₂ H H 2-F 3-H 4-H 6-H 5 H

ok 173 Phenyl-2,4-Cl₂ H H 2-F 3-H 4-H 6-H 5 H

ok 174 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 175 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 176 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₂—COOH ok 177Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₃—COOH ok 178 Phenyl-2-ClH H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 179 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 180 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 181 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₄—COOH ok 182Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₅—COOH ok 183 Phenyl-2-ClH H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 184 Phenyl-2-Cl H H 2-OCH₃ 3-H 4-H 6-H 5 H (CH₂)₄—COOH ok 185Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 186 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 187 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H (CH₂)₅—OH ok 188Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H (CH₂)₆—OH ok 189 Phenyl-2-Cl H H2-NO₂ 3-H 5-H 6-H 4 H

ok 190 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 191 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 192 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 193 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 194 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 195 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 196 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 197 Phenyl-2-Cl H H 2-H 3-Cl 5-H 6-H 4 H

ok 198 Phenyl-2-Cl H H 2-H 3-Cl 5-H 6-H 4 H (CH₂)₅—OH ok 199 Phenyl-2-ClH H 2-H 3-Cl 5-H 6-H 4 H

ok 200 Phenyl-2-Cl H H 2-H 3-Cl 5-H 6-H 4 H

ok 201 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H (CH₂)₅—OH ok 202 Phenyl-2-ClH H 2-H 3-H 5-H 6-H 4 H (CH₂)₆—OH ok 203 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H4 H

ok 204 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 205 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 206 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 207 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 208 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 209 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 210 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 211 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-Cl 4 H (CH₂)₆—OH ok 212Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-Cl 4 H (CH₂)₅—OH ok 213 Phenyl-2-Cl H H2-Cl 3-H 5- 6-H 4 H (CH₂)₅—OH ok OCH₃ 214 Phenyl-2-Cl H H 2-Cl 3-H 5-6-H 4 H (CH₂)₆—OH ok OCH₃ 215 Phenyl-2-Cl H H 2-Cl 3-H 5- OCH₃ 6-H 4 H

ok 216 Phenyl-2-Cl H H 2-Cl 3-H 5- OCH₃ 6-H 4 H

ok 217 Phenyl-2-Cl H H 2-Cl 3-H 5- OCH₃ 6-H 4 H

ok 218 Phenyl-2-Cl H H 2-Cl 3-H 5- OCH₃ 6-H 4 H

ok 219 Phenyl-2-Cl H H 2-Cl 3-H 5- OCH₃ 6-H 4 H

ok 220 Phenyl-2-Cl H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 221 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 222 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H

ok 223 Phenyl-2-Cl H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₅—OH ok 224Phenyl-2-Cl H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₆—OH ok 225 Phenyl-2-Cl H H2-OCH₃ 3-H 5-H 6-H 4 H

ok 226 Phenyl-2-Cl H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 227 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H (CH₂)₅—OH ok 228 Phenyl-2-ClH H 2-Cl 3-H 5-H 6-H 4 H (CH₂)₆—OH ok 229 Phenyl-2-Cl H H 2-Cl 3-H 5-H6-H 4 H

ok 230 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H

ok 231 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H

ok 232 Phenyl-2-Cl H H 2-F 3-F 5-F 6-F 4 H (CH₂)₅—OH ok 233Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₅—OH ok 234Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₆—OH ok 235Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 236 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 237 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 238 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 239 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 240 Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H (CH₂)₅—OH ok 241Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H (CH₂)₆—OH ok 242 Phenyl-2,4-Cl₂H H 2-Cl 3-H 5-H 6-H 4 H

ok 243 Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H

ok 244 Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H

ok 245 Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H

ok 246 Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H

ok 247 Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H

ok 248 Phenyl-2,4-Cl₂ H H 2-OH 3-H 5-H 6-H 4 H (CH₂)₆—OH ok 249Phenyl-2,4-Cl₂ H H 2-NO₂ 3-H 5-H 6-H 4 H

ok 250 Phenyl-2-Cl H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 251 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H

ok 252 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H

ok 253 Phenyl-2,4-Cl₂ H H 2-Cl 3-H 5-H 6-H 4 H

ok 254 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 4-H 6-H 5 H

ok 255 Phenyl-2-Cl-4-F H H 2-OCH₃ 3-H 5-H 6-H 4 H H ok 256Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H H ok 257 Phenyl-2-Cl-4-F H H2-OCH₃ 3-H 5-H 6-H 4 H CH₃ ok 258 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H4 H CH₃ ok 259 Phenyl-2-Cl-4-F H H 2-OCH₃ 3-H 5-H 6-H 4 H(CH₂)₃—NHCOO—CH₂-Ph ok 260 Phenyl-2-Cl-4,5-F₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H(CH₂)₃—NHCOO—CH₂-Ph ok 261 Phenyl-2-Cl-4-F H H 2-OCH₃ 3-H 5-H 6-H 4 CH₃CH₃ ok 262 Phenyl-2,4-Cl₂ H H 2-OCH₃ 3-H 5-H 6-H 4 CH₃ CH₃ ok 263Phenyl-2-Cl-4,5-F₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H CH₃ ok 264Phenyl-2-Cl-4,5-F₂ H H 2-OCH₃ 3-H 5-H 6-H 4 CH₃ CH₃ ok 265Phenyl-2-Cl-4,5-F₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₂—NHCO—CH₃ ok 266Phenyl-2-Cl-4,5-F₂ H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₃—NH₂ ok TFA 267Phenyl-2-Cl-4,5-F₂ H H 2-Cl 3-H 5-H 6-H 4 H CH₃ ok 268Phenyl-2-Cl-4,5-F₂ H H 2-Cl 3-H 5-H 6-H 4 CH₃ CH₃ ok 269Phenyl-2-Cl-4,5-F₂ H H 2-Cl 3-H 5-H 6-H 4 H H ok 270 Phenyl-2-Cl-4,5-F₂H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₃—N(CH₃)₂ ok TFA 271 Phenyl-2-Cl-4,5-F₂H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₂—N(CH₃)₂ ok TFA 272 Phenyl-2,4-Cl₂ H H2-Cl 3-H 5-H 6-H 4 H (CH₂)₂—NHCOO—CH₂— ok CH═CH₂ 273 Phenyl-2-Cl-4,5-F₂H H 2-OCH₃ 3-H 5-H 6-H 4 H (CH₂)₄—NH₂ ok TFA 274 Phenyl-2,4-Cl₂ H H 2-Cl3-H 5-H 6-H 4 H (CH₂)₂—NH₂ ok TFA 275 Phenyl-2-Cl-4-F H H 2-OCH₃ 3-H 5-H6-H 4 H (CH₂)₃—NH₂ ok TFA 276 Phenyl-2-Cl-4,5-F₂ H H 3-H 4-H 5- 6-H 2 HCH₃ ok COOH 277 Phenyl-2-Cl-4,5-F₂ H H 2-OCF₃ 3-H 5-H 6-H 4 H CH₃ ok 278Phenyl-2-Cl-4,5-F₂ H H 2-OCF₃ 3-H 5-H 6-H 4 CH₃ CH₃ ok 279Phenyl-2-Cl-4,5-F₂ H H 3-H 4-H 5-H 6-H 2 H H ok 280 Phenyl-2-Cl-4,5-F₂ HH 2-OCF₃ 3-H 5-H 6-H 4 H CH₂—COO—CH₃ ok 281 Phenyl-2-Cl-4,5-F₂ H H2-OCF₃ 3-H 5-H 6-H 4 CH₃ CH₂—COO—CH₃ ok 282 Phenyl-2-Cl-4,5-F₂ H H2-OCF₃ 3-H 5-H 6-H 4 H (CH₂)₂—COO—CH₃ ok 283 Phenyl-2-Cl-4,5-F₂ H H2-OCF₃ 3-H 5-H 6-H 4 H (CH₂)₃—COO—CH₃ ok 284 Phenyl-2-Cl-4,5-F₂ H H2-OCF₃ 3-H 5-H 6-H 4 H CH₂—COOH ok 285 Phenyl-2-Cl-4,5-F₂ H H 2-OCF₃ 3-H5-H 6-H 4 CH₃ CH₂—COOH ok 286 Phenyl-2-Cl-4,5-F₂ H H 2-OCF₃ 3-H 5-H 6-H4 H (CH₂)₂—COOH ok 287 Phenyl-2-Cl-4,5-F₂ H H 2-OCF₃ 3-H 5-H 6-H 4 H(CH₂)₃—COOH ok

[0131] The compounds of the formula I are distinguished by beneficialeffects on glucose metabolism; in particular they lower the bloodglucose level and are suitable for treating type II diabetes. Thecompounds can be employed alone or in combination with other bloodglucose-lowering active ingredients (antidiabetics). Examples of suchblood glucose-lowering active ingredients are sulfonylureas (such as,for example, glimepiride, glibenclamide, gliclazide, glibornuride,gliquidone, glisoxepide), metformin, tolbutamide, glitazones (such as,for example, troglitazone, rosiglitazone, pioglitazone, repaglinide),alpha-glucosidase inhibitors (such as, for example, acarbose, miglitol)or insulins. All antidiabetics mentioned in chapter 12 of the Rote Liste2001 can be combined with the compounds of the formula I of theinvention for improving the effect. Administration of the activeingredient combination can take place either by separate administrationof the active ingredients to the patients or in the form of combinationproducts in which a plurality of active ingredients are present in onepharmaceutical preparation.

[0132] The compounds of the formula I are additionally suitable for thetreatment of late complications of diabetes such as, for example,nephropathy, retinopathy, neuropathy and mycocardial infarction,peripheral arterial occlusive diseases, thromboses, arteriosclerosis,syndrome X, obesity, inflammations, immune diseases, autoimmune diseasessuch as, for example, AIDS, asthma, osteoporosis, cancer, psoriasis,Alzheimer's, schizophrenia and infectious diseases.

[0133] The activity of the compounds was assayed as follows:

[0134] Glycogen Phosphorylase a Activity Assay

[0135] The effect of compounds on the activity of the active form ofglycogen phosphorylase (GPa) was measured in the reverse direction byfollowing the synthesis of glycogen from glucose 1-phosphate bydetermining the liberation of inorganic phosphate. All the reactionswere carried out as duplicate determinations in microtiter plates with96 wells (Half Area Plates, Costar No 3696), measuring the change inabsorption owing to the formation of the reaction product at thewavelength specified hereinafter in a Multiskan Ascent Elisa Reader (LabSystems, Finland). In order to measure the GPa enzymic activity in thereverse direction, the general method of Engers et al. (Engers HD,Shechosky S, Madsen NB, Can J Biochem July 1970;48(7):746-754) was usedto measure the conversion of glucose 1-phosphate into glycogen andinorganic phosphate, with the following modifications: human glycogenphosphorylase a (for example with 0.76 mg of protein/ml (Aventis PharmaDeutschland GmbH), dissolved in buffer solution E (25 mMβ-glycerophosphate, pH 7.0,1 mM EDTA and 1 mM dithiothreitol) wasdiluted with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, 2.5mM MgCl₂·6H₂O) and addition of 5 mg/ml glycogen to a concentration of 10μg of protein/ml. Test substances were prepared as 10 mM solution inDMSO and diluted to 50 μM with buffer solution T. To 10 μl of thissolution were added 10 μl of 37.5 mM glucose, dissolved in buffersolution T, and 5 mg/ml glycogen, plus 10 μl of a solution of humanglycogen phosphorylase a (10 μg of protein/ml) and 20 μl of glucose1-phosphate, 2.5 mM. The baseline glycogen phosphorylase a activity inthe absence of test substance was determined by adding 10 μl of buffersolution T (0.1% DMSO). The mixture was incubated at room temperaturefor 40 minutes, and the liberated inorganic phosphate was measured bythe general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D,Anal Biochem Sep. 1, 1995;230(1):173-177) with the followingmodifications: 50 μl of a stop solution of 7.3 mM ammonium molybdate,10.9 mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS are added to 50 μl ofthe enzyme mixture. After incubation at 45° C. for 60 minutes, theabsorption at 820 nm was measured. To determine the backgroundabsorption, in a separate mixture the stop solution was addedimmediately after addition of the glucose 1-phosphate solution.

[0136] This test was carried out with a concentration of 10 μM of thetest substance in order to determine the particular inhibition ofglycogen phosphorylase a in vitro by the test substance. TABLE 2Biological activity: % inhibition at Ex. 10 μM 1 87 2 73 3 75 4 79 5 7712 92 20 35 29 78 30 76 31 86 41 50 44 11 46 36 47 46 49 13 51 36 53 2260 36 70 86 75 41 80 50 84 44 89 90 90 34 100 78 101 93 102 14 106 35111 88 112 100 116 100 117 99 118 70 119 97 120 40 122 12 128 95 147 88149 76

[0137] It is to be inferred from the table that the compounds of theformula I inhibit the activity of glycogen phosphorylase a and are thusvery suitable for lowering the blood glucose level.

[0138] The preparation of some examples is described in detail below,and the other compounds of the formula I were obtained analogously:

[0139] Experimental Part:

EXAMPLE 1

[0140] a) 2-Chlorobenzoyl Isocyanate

[0141] 2-Chlorobenzamide was dissolved in dichloromethane, mixed with1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. Thereaction mixture was concentrated under high vacuum and reacted in stageb without further purification.

[0142] b) 4-Chloro-3-[3-(2-chlorobenzoyl)ureido]benzoic Acid

[0143] 1 g (5.8 mmol) of 3-amino-4-chlorobenzoic acid were mixed with0.75 g (5.8 mmol) of diisopropylethylamine and 1.06 g (5.8 mmol) of2-chlorobenzoyl isocyanate in 5 ml of dichloromethane and reacted atroom temperature for 12 hours. The solvent was evaporated, the residuewas mixed with 5% strength sodium bicarbonate solution and extractedtwice with diethyl ether, and the aqueous phase was adjusted to pH 3with HCl. The resulting precipitate was filtered off with suction.

[0144] c) Ethyl4-{4-chloro-3-[3-(2-chlorobenzoyl)ureido]benzoylamino}piperidine-1-carboxylate

[0145] 100 mg (0.28 mmol) of4-chloro-3-[3-(2-chlorobenzoyl)ureido]benzoic acid, 93 mg (0.28 mmol) ofTOTU and 37 mg (0.28 mmol) of diisopropylethylamine were coupled in 1 mlof dimethylformamide. The reaction solution was washed once each with 5%strength sodium bicarbonate solution and 10% strength citric acidsolution, and the organic phase was dried and concentrated.

[0146] Examples 2-52 and 188-220 were synthesized in analogy to example1.

EXAMPLE 94

[0147] a) 4-[3-(2,4-Dichlorobenzoyl)ureido]-3-methoxybenzoic Acid

[0148] 36.1 g (167.5 mmol) of 2,4-dichlorobenzoyl isocyanate, which wasprepared in analogy to example 1a, were added to a solution of 20 g(119.6 mmol) of 4-amino-3-methoxybenzoic acid in 400 ml of acetonitrile.The mixture was heated to reflux for 2 hours and cooled to roomtemperature. The precipitate was filtered off with suction, washed withacetonitrile and methanol, stirred with 5% strength potassium bisulfatesolution, again filtered off with suction and dried under high vacuum.44 g (96%) of the desired product were obtained.

[0149] b) 4-[3-(2,4-Dichlorobenzoyl)ureido]-3-methoxybenzoyl Chloride

[0150] 11.25 g (37.2 mmol) of4-[3-(2,4-dichlorobenzoyl)ureido]-3-methoxybenzoic acid from stage awere heated to reflux with 150 ml of thionyl chloride for 3 hours andevaporated in a rotary evaporator under high vacuum. The residue wastwice mixed with toluene and again evaporated under high vacuum toresult in 10.88 g (27.09 mmol, 73%) of acid chloride (loss due tofoaming over). The product obtained in this way was employed in the nextstage without further purification.

[0151] c)3-[3-(2,4-Dichlorobenzoyl)ureido]-4-methoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamideSodium Salt

[0152] A suspension of 157 mg (0.39 mmol) of acid chloride from stage band 4 ml of dichloromethane was added to a solution of 65 μl (0.8 mmol)of pyridine and 63 mg (0.4 mmol) of2,2,6,6-tetramethylpiperidin-4-ylamine in 2 ml of dichloromethane, andthe reaction mixture was reacted at room temperature for 16 hours. Thereaction mixture was diluted with 2.5 ml of acetonitrile, filtered andwashed with 5 ml of acetonitrile, and the filtrate was evaporated. Theresidue was taken up in a mixture of 2N of sodium hydroxide solution,acetonitrile and dimethylformamide (1/2/2), whereupon the productprecipitated.

[0153] Examples 95-152 were synthesized in analogy to example 94. Ifrequired, the products were purified by preparative reverse phase HPLC(acetonitrile/water/TFA).

We claim:
 1. A compound of the formula I,

in which A is phenyl or naphthyl, where the phenyl or naphthyl isunsubstituted or substituted 1, 2, or 3 times wherein each substituentis independently chosen from F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀C₆)-alkylene-COOH,(C₀C₆)-alkylene-COO—(C₁-C₇)-alkyl, (C₀-C₆)-alkylene-COO—(C₂-C₇)-alkenyl,CONH₂, CONH—(C₁-C₆)-alkyl, CON—[(C₁-C₆)-alkyl]₂,CONH—(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀C₆)-alkylene-NH—(C₂-C₆)-alkyl, (C₀C₆)-alkylene-N—[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, and NH—SO₂-phenyl, wherein the phenylof NH—CO-phenyl and NH—SO₂-phenyl is unsubstituted or substituted 1 or 2times wherein each substituent is independently chosen from F, Cl, CN,OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyland CONH₂; R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, or COO—(C₁-C₆)-alkyl; R3, R4, R5, R6are, independently of one another, H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂,CO—NH—(C₁-C₆)-alkyl, CO—N—[(C₁-C₆)-alkyl]₂, CO—NH—(C₃-C₇)-cycloalkyl,NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenyl of NH—CO-phenyl andNH—SO₂-phenyl is unsubstituted or substituted 1 or 2 times wherein eachsubstituent is independently chosen from F, Cl, CN, OH, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl and CO—NH₂; R7 is H,(C₁-C₆)-alkyl, or CO(C₁-C₆)-alkyl; R8 is H, (C₁-C₁₀)-alkyl, where thealkyl is unsubstituted or substituted 1, 2, or 3 times wherein eachsubstituent is independently chosen from OH, CF₃, CN, COOH,COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂,NCO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl,NCOO—(C₁-C₆)-alkynyl and NCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or (CH₂)_(m)-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl,CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl,piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,or morpholinyl, where the aryl is unsubstituted or substituted by atleast one R9; R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COOH, or COO—(C₁-C₆)-alkyl; or a physiologically tolerable salt thereof,in any stereoisomeric form, or a mixture of any such compounds in anyratio.
 2. The compound as claimed in claim 1, in which A is phenyl,where the phenyl is unsubstituted or substituted 1, 2, or 3 timeswherein each substituent is independently chosen from F, Cl, and Br; R1,R2 are H; R3, R4, R5, R6 are, independently of one another, H, F, Cl,Br, NO₂, O—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl; R7 is H, or CH₃; R8 is H,(C₁-C₁₀)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or3 times wherein each substituent is independently chosen from OH, CF₃,CN, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂, NH—(C₁-C₆)-alkyl,N—[(C₁-C₆)-alkyl]₂, NCO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkyl,NCOO—(C₁-C₆)-alkenyl, NCOO—(C₁-C₆)-alkynyl orNCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or  (CH2)_(m)-aryl, where m rangesfrom 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl,heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl,naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl,pyrrolidinyl, morpholinyl, where the aryl is unsubstituted orsubstituted by at least one R9; R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,(C₁-C₄)-alkylphenyl, COOH, or COO—(C₁-C₆)-alkyl; or a pharmaceuticallytolerable salt thereof, in any stereoisomeric form, or a mixture of anysuch compounds in any ratio.
 3. The compound as claimed in claim 1, inwhich A is phenyl, where the phenyl is unsubstituted or substituted 1,2, or 3 times wherein each substituent is independently chosen from F,Cl, and Br; R1,R2 are H; R3, R4, R5, R6 are, independently of oneanother, H, F, Cl, Br, NO₂, O—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl; R7 is H,or CH_(3;) R8 is (C₁-C₁₀)-alkyl, where the alkyl is unsubstituted orsubstituted 1, 2, or 3 times wherein each substituent is independentlychosen from OH, CF₃, CN, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂,NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NCO—(C₁-C₆)-alkyl,NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl, NCOO—(C₁-C₆)-alkynyl orNCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or  (CH₂)_(m)-aryl, where m rangesfrom 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl,heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl,naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl,pyrrolidinyl, morpholinyl, where the aryl is unsubstituted orsubstituted by at least one R9; R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,(C₁-C₄)-alkylphenyl, COOH, or COO—(C₁-C₆)-alkyl; or a pharmaceuticallytolerable salt thereof, in any stereoisomeric form, or a mixture of anysuch compounds in any ratio.
 4. A medicament, comprising at least onecompound as claimed claim 1 and at least one pharmaceutically acceptablecarrier.
 5. A medicament, comprising at least one compound as claimedclaim 1, at least one additional blood glucose-lowering activeingredient, and at least one pharmaceutically acceptable carrier.
 6. Amethod for treating type II diabetes comprising, administering to apatient in need thereof at least one compound as claimed claim 1 and atleast one additional blood glucose-lowering active ingredients.
 7. Themethod of treating type II diabetes of claim 6, wherein the at least onecompound as claimed claim 1 and the at least one additional bloodglucose-lowering active ingredients are administered sequentially.
 8. Amethod for lowering blood glucose comprising, administering to a patientin need thereof at least one compound as claimed claim 1 and at leastone additional blood glucose-lowering active ingredients.
 9. The methodfor lowering blood glucose of claim 8, wherein the at least one compoundas claimed claim 1 and the at least one additional bloodglucose-lowering active ingredients are administered sequentially.
 10. Aprocess for producing a medicament comprising at least one compound asclaimed claim 1, which comprises mixing the at least one compound asclaimed claim 1 with a pharmaceutically suitable carrier and convertingthis mixture into a form suitable for administration.
 11. A method oflowering blood glucose comprising administering to a patient in needthereof at least one compound chosen from compounds of the formula I,

in which A is phenyl or naphthyl, where the phenyl or naphthyl isunsubstituted or substituted 1, 2, or 3 times wherein each substituentis independently chosen from F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene-COO—(C₁-C₇)-alkyl,(C₀-C₆)-alkylene-COO—(C₂-C₇)-alkenyl, CONH₂, CONH—(C₁-C₆)-alkyl,CON—[(C₁-C₆)-alkyl]₂, CONH—(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH—(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N—[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, and NH—SO₂-phenyl, wherein the phenylof NH—CO-phenyl and NH—SO₂-phenyl is unsubstituted or substituted 1 or 2times wherein each substituent is independently chosen from F, Cl, CN,OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyland CONH₂; R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, or COO—(C₁-C₆)-alkyl; R3, R4, R5, R6are, independently of one another, H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂,CO—NH—(C₁-C₆)-alkyl, CO—N—[(C₁-C₆)-alkyl]₂, CO—NH—(C₃-C₇)-cycloalkyl,NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenyl of NH—CO-phenyl andNH—SO₂-phenyl is unsubstituted or substituted 1 or 2 times wherein eachsubstituent is independently chosen from F, Cl, CN, OH, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl and CO—NH₂; R7 is H,(C₁-C₆)-alkyl, or CO(C₁-C₆)-alkyl; R8 is H, (C₁-C₁₀)-alkyl, where thealkyl is unsubstituted or substituted 1,2, or 3 times wherein eachsubstituent is independently chosen from OH, CF₃, CN, COOH,COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂,NCO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl,NCOO—(C₁-C₆)-alkynyl and NCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or (CH₂)_(m)-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl,CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl,piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,or morpholinyl, where the aryl is unsubstituted or substituted by atleast one R9; R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COOH, or COO—(C₁-C₆)-alkyl; and physiologically tolerable salts thereof,in any stereoisomeric form, and any mixture of any such compounds in anyratio.
 12. A method for treating type II diabetes comprisingadministering to a patient in need thereof at least one compound chosenfrom compounds of the formula I,

in which A is phenyl or naphthyl, where the phenyl or naphthyl isunsubstituted or substituted 1, 2, or 3 times wherein each substituentis independently chosen from F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₀-C₆)-alkylene-COOH,(C₀-C₆)-alkylene-COO—(C₁-C₇)-alkyl,(C₀-C₆)-alkylene-COO—(C₂-C₇)-alkenyl, CONH₂, CONH—(C₁-C₆)-alkyl,CON—[(C₁-C₆)-alkyl]₂, CONH—(C₃-C₆)-cycloalkyl, (C₀-C₆)-alkylene-NH₂,(C₀-C₆)-alkylene-NH—(C₂-C₆)-alkyl, (C₀-C₆)-alkylene-N—[(C₁-C₆)-alkyl]₂,NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl, and NH—SO₂-phenyl, wherein the phenylof NH—CO-phenyl and NH—SO₂-phenyl is unsubstituted or substituted 1 or 2times wherein each substituent is independently chosen from F, Cl, CN,OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyland CONH_(2;) R1, R2 are, independently of one another, H,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, or COO—(C₁-C₆)-alkyl;R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl,S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, COOH, COO—(C₁-C₆)-alkyl, CO—NH₂,CO—NH—(C₁-C₆)-alkyl, CO—N—[(C₁-C₆)-alkyl]₂, CO—NH—(C₃-C₇)-cycloalkyl,NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl, or NH—SO₂-phenyl, wherein the phenyl of NH—CO-phenyl andNH—SO₂-phenyl is unsubstituted or substituted 1 or 2 times wherein eachsubstituent is independently chosen from F, Cl, CN, OH, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl and CO—NH₂; R7 is H,(C₁-C₆)-alkyl, or CO(C₁-C₆)-alkyl; R8 is H, (C₁-C₁₀)-alkyl, where thealkyl is unsubstituted or substituted 1, 2, or 3 times wherein eachsubstituent is independently chosen from OH, CF₃, CN, COOH,COO—(C₁-C₆)-alkyl, CO—NH₂, NH₂, NH—(C₁-C₆)-alkyl, N—[(C₁-C₆)-alkyl]₂,NCO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkyl, NCOO—(C₁-C₆)-alkenyl,NCOO—(C₁-C₆)-alkynyl and NCOO—(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl; or (CH₂)_(m)-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl,CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl,piperidinyl, tetrahydronaphthyl, naphthyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl,or morpholinyl, where the aryl is unsubstituted or substituted by atleast one R9; R9 is F, Cl, Br; OH, NO₂, CF₃, OCF₃, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₄)-alkylphenyl,COOH, or COO—(C₁-C₆)-alkyl; and physiologically tolerable salts thereof,in any stereoisomeric form, and any mixture of any such compounds in anyratio.